This invention relates to a novel process for the preparation of the compound of formula

The compound is suitable to introduce a new functionality in the C-4″ position of the cladinose ring of azaerythromycin A, typically a third basic amine group or other heteroatom functionality.
A further object of the invention are the novel intermediates of the process of the invention. These novel compounds may be isolated in crystalline form as stable solids with high yield and purity.
Macrolides are a well known class of antibiotics. Clarithromycin and azithromycin have been used for the treatment of human respiratory infections caused by a variety of pathogens for quite a long time. Most recently, Tulathromycin has been approved for the treatment and prevention of bacterial respiratory disease in cattle and pigs. Tulathromycin is a 15-membered azalide antibiotic of the formula

Processes for the preparation of Tulathromycin, known, for example, from in EP 0988310 or EP 1253153, use 9-deoxo-9a-aza-9a-homoerythromycin A (azaerythromycin A) as starting material. Following protection of the amino group 9a and the hydroxyl group C-2′ with benzylchloroformate, the hydroxyl group in 4-position is oxidized and following deprotection converted into the epoxide of formula (1) above, which is in turn converted to Tulathromycin by reaction of the epoxide group with n-propylamine.
The main drawbacks of the known synthesis are:    (i) The use of highly toxic benzylchloroformate as protecting agent, which is known to be a human carcinogen by itself or as a consequence of the impurities usually contaminating this reagent. On the other hand, it is classified as a marine pollutant thus raising additional safety concerns specially when handling at industrial scale.    (ii) The isolation and purification of process of intermediates and the Tulathromycin requires laborious column chromatography in order to remove impurities and side products formed during the reactions.    (iii) Catalytic hydrogenation for three days is necessary to remove protective groups introduced after the oxidation step. This hydrogenation is carried out in presence of toxic class 1 metals (i.e.: Paladium) which need to be adequately removed to very low levels and not carried over into the Tulathromycin.    (iv) The instability of azalides, in particular if the nitrogen in the 9a position is not methylated, causes degradation of the 15-membered azalide backbone, as well known and documented in the literature.
Therefore, the need for an improved process for the production of Tulathromycin, which is feasible on an industrial scale does exist. It now has surprisingly been found a smooth, upscaleable synthesis for Tulathromycin and its precursor of the above formula (1) starting from erythromycin A 9-(E)-oxime instead of azaerythromycin A.